Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

2D QSAR Analysis of Substituted Quinoxalines for their Antitubercular and Antileptospiral Activities

Author(s): Ramalakshmi Natarajan*, Ayarivan Puratchikody, Vignesh Muralidharan, Mukesh Doble* and Arunkumar Subramani

Volume 15, Issue 2, 2019

Page: [182 - 192] Pages: 11

DOI: 10.2174/1573409914666181011145922

Price: $65

Abstract

Background: The Quantitative structure activity relationship for thirty two novel substituted quinoxalines was performed for their antitubercular (Mycobacterium tuberculosis H37Rv) and antileptospiral (Leptospirainterrogans) activities. The quinoxalines were substituted with azetidinones, thiazolidinones and fluoroquinolones. Several compounds exhibited good activity against both the infections and they all possess fluoroquinolone moiety with the quinoxaline.

Methods: The models developed showed good linear relationship (r2 = 0.71-0.88), with an internal predictive ability (q2> 0.61) and good external predictive ability (pred_r2>0.71). The compounds were separated into a training set on which regression was performed and a test set on which the predictive ability of the model was tested. Other statistical parameters including Ro2, Ro’2, k, k’ and Z- score were in the acceptable range.

Results and Conclusion: The descriptors obtained explained the necessity of spatial orientation of atoms including branching and adjacency, presence of electronegative groups, balance between lipophilic elements and their binding strengths.

Keywords: Quinoxaline, antileptospiral, antitubercular, QSAR analysis, electronegative groups, lipophilic elements.

« Previous
Graphical Abstract

[1]
Neil, K.M.; Rickman, L.S.; Lazarus, A.A. Pulmonary manifestations of leptospirosis. Rev. Infect. Dis., 1991, 13, 705-709.
[2]
Bharti, A.R.; Nally, J.E.; Ricaldi, J.N.; Matthias, M.A.; Diaz, M.M.; Lovett, M.A.; Levett, P.N.; Gilman, R.H.; Willig, M.R.; Gotuzzo, E. Leptospirosis: A zoonotic disease of global importance. Lancet Infect. Dis., 2003, 3, 757-771.
[3]
Gupta, R.A.; Gupta, A.K.; Soni, L.K.; Kaskhedikar, S. Rationalization of physicochemical characters of oxazolyl thiosemicarbazone analogs towards multi-drug resistant tuberculosis: A QSAR approach. Eur. J. Med. Chem., 2007, 42, 1109-1116.
[4]
Sivakumar, P.M.; Geethababu, S.K.; Doble, M. Impact of topological and electronic descriptors in the QSAR of pyrazine containing thiazolines and thiazolidinones as antitubercular and antibacterial agents. Chem. Biol. Drug Des., 2008, 71, 447-463.
[5]
Vicente, E.; Perez-Silanes, S.; Lima, L.M.; Ancizu, S.; Burguete, A.; Solano, B.; Villar, R.; Aldana, I.; Monge, A. Selective activity against Mycobacterium tuberculosis of new quinoxaline 1,4-di-N-oxides. Bioorg. Med. Chem., 2009, 17, 385-389.
[6]
Lee, J.S.; Waring, M.J. Interaction between synthetic analogues of quinoxaline antibiotics and nucleic acids. Changes in mechanism and specificity related to structural alterations. Biochem. J., 1978, 173, 129-144.
[7]
Seitz, L.E.; Suling, W.J.; Reynolds, R.C. Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives. J. Med. Chem., 2002, 45, 5604-5606.
[8]
Sharma, M.; Sahu, N.; Kohli, D.; Chaturvedi, S.; Sharma, S. Synthesis, characterization and biological activities of some 1-(nicotinylamino)-2 substituted azetidine-4-ones as potential antibacterial agents. Dig. J. Nanomater. Biostruct., 2009, 4, 361-367.
[9]
Jarrahpour, A.; Zarei, M. Synthesis of novel N-sulfonyl monocyclic β-lactams as potential antibacterial agents. Molecules, 2006, 11, 49-58.
[10]
Vijayakumar, M.M.J.; Nagaraja, T.; Shameer, H.; Jayachandran, E.; Sreenivasa, G. N-Substituted-3-chloro-2-azetidinones: Synthesis and characterization of new novel anti-inflammatory agents. J. Pharm. Sci., 2009, 1, 83-92.
[11]
Verma, A.; Saraf, S.K. 4-Thiazolidinone-a biologically active scaffold. Eur. J. Med. Chem., 2008, 43, 897-905.
[12]
Puratchikody, A.; Natarajan, R.; Jayapal, M.; Doble, M. Synthesis, in vitro antitubercular activity and 3D‐QSAR of novel quinoxaline derivatives. Chem. Biol. Drug Des., 2011, 78, 988-998.
[13]
Golbraikh, A.; Tropsha, A. Beware of q2! J. Mol. Graph. Model., 2002, 20, 269-276.
[14]
Sivakumar, P.M.; Iyer, G.; Doble, M. QSAR studies on substituted 3-or 4-phenyl-1, 8-naphthyridine derivatives as antimicrobial agents. Med. Sci. Res., 2011, 21, 788-7958.
[15]
Baumann, K. An alignment-independent versatile structure descriptor for QSAR and QSPR based on the distribution of molecular features. J. Chem. Inf. Comput. Sci., 2002, 42, 26-35.
[16]
Goffin, C.; Ghuysen, J.M. Biochemistry and comparative genomics of SxxK superfamily acyltransferases offer a clue to the mycobacterial paradox: Presence of penicillin-susceptible target proteins versus lack of efficiency of penicillin as therapeutic agent. Microbiol. Mol. Biol. Rev., 2002, 66, 702-738.
[17]
Sanna, P.; Carta, A.; Nikookar, M.E.R. Synthesis and antitubercular activity of 3-aryl substituted-2-(1H (2H) benzotriazol-1 (2)-yl) acrylonitriles. Eur. J. Med. Chem., 2000, 35, 535-543.
[18]
Hall, L.H.; Kier, L.B. Issues in representation of molecular structure: The development of molecular connectivity. J. Mol. Graph. Model., 2001, 20, 4-18.
[19]
Gough, J.D.; Lowell, H. Modeling antileukemic activity of carboquinones with electrotopological state and chi indices. J. Chem. Inf. Comput. Sci., 1999, 39, 356-361.
[20]
Shalit, I.; Barnea, A.; Shahar, A. Efficacy of ciprofloxacin against Leptospira interrogans serogroup icterohaemorrhagiae. Antimicrob. Agents Chemother., 1989, 33, 788-789.
[21]
Bal, A.M. Use of ciprofloxacin for treating leptospirosis–need for clinical trials. J. Med. Microbiol., 2005, 54, 907-907.
[22]
Ravichandran, V.; Harish, R.; Abhishek, J.; Shalini, S.; Christapher, P. Varghese.; Ram, K.A. Validation of QSAR models - strategies and importance. Int. J. Drug Discov., 2011, 3(2), 511-519.
[23]
Sharma, M.C.; Smita, S. 2D QSAR study of 7-methyljuglone derivatives: An approach to design anti tubercular agents. J. Pharm. Toxico., 2011, 6, 493-504.
[24]
Kunal, R.; Asim, S.M. Development of linear and nonlinear predictive QSAR models and their external validation using molecular molecular similarity principle for anti-HIV indolyl aryl sulfones. J. Enzyme Inhib. Med. Chem., 2008, 23 6, 980-995

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy